Post of the Week: All About Rasagiline

What is rasagiline? Is it merely a more expensive version of selegiline?

Rasagiline is a new selective MAO-B inhibitor that can be differentiated from selegiline by chemical structure, route of metabolism, metabolites, and its side effect profile. First, selegiline is given twice per day, while rasgailine can be taken once per day. When selegiline is metabolized (or broken down into by products), its metabolites are amphetamine derivatives. Rasagiline is not broken down into amphetamine metabolites. Therefore, theoretically, rasagiline avoids the risk of the amphetamine stimulant-related side effects, such as hallucinations and sleep disturbance, and cardiovascular instability that have been associated or implicated with selegiline use (Stern et al 2004). Because selegiline is available in generic form, while rasagiline is not, rasagiline is clearly more expensive than its older predecessor.

Rasagiline seems to have a lot of restrictions. Can I trust the drug? What is it really used for?

Rasagiline is actually one of the most well-studied medications we have for the treatment of Parkinson’s disease symptoms. Rasagiline clinical trials have demonstrated its efficacy and safety both as initial therapy and as adjunct (or “add on”) therapy. Rasagiline is FDA approved for use in both early and advanced Parkinson’s disease.

Rasagiline as an initial therapy for patients with early PD was evaluated in a Phase III, multi-center, double-blind (meaning both the clinician and the patient did not know whether the patient was given the real drug or not), placebo-controlled, 1-year, “delayed-start” trial called TEMPO [(TVP-1012) in Early Monotherapy for Parkinson’s disease Outpatients]. The TEMPO trial examined rasagiline’s efficacy as initial therapy in 404 patients with early PD not yet requiring dopaminergic therapy (Parkinson Study Group 2002; Parkinson Study Group 2004). The primary outcome measure for the first phase was the change in total Parkinson motor score before and after treatment, comparing rasagiline with placebo. Analysis of the Parkinson motor scores revealed that patients treated with rasagiline had better overall function compared to the placebo group (Parkinson Study Group 2002).

As for its usefulness as an add on treatment to levodopa on patient who are experiencing wearing off, two large multi-center studies were performed: Parkinson’s Rasagiline: Efficacy and Safety in the Treatment of OFF (PRESTO) and Lasting effect in Adjunct therapy with Rasagiline Given Once daily (LARGO) (Parkinson Study Group 2005; Rascol et al 2005). Both studies showed significant decreases in daily off time with rasagiline compared with placebo, as well as significant improvements in global impression, activities of daily living Parkinson motor scores.

Do I really need to avoid eating cheese and pepperoni when I take rasagiline? I love pizza!

This food scare came about because historically the earlier MAO inhibitors were “non-selective”, meaning, they blocked both type A and type B enzymes. Only the type B enzymes are generally confined to the brain. The type A enzymes are abundantly distributed throughout the body, especially in the gut. They are good enzymes that ‘guard’ and block a substance called “tyramine” from getting absorbed in the gut and entering the blood stream in large quantities. Therefore, once an MAO-type A inhibitor medication is ingested, then the ‘road block’ to tyramine created by the enzymes becomes lifted giving tyramine a free pass to cross the gut and enter the blood stream. This can result in a severe and abrupt rise in blood pressure (what we call “hypertensive crisis”). Thus, foods rich in tyramine have been traditionally banned when using a non-selective MAO inhibitor, because they inhibit the type A enzymes.

The good news is that selegiline and rasgiline are selective MAO-B inhibitors. Therefore, at their recommended doses, they do not block the type A enzymes, they only block the type B enzymes. Thus in our opinion, it is generally safe to eat any type of food (of course in moderation) whether or not they are rich in tyramine. In fact, during the pivotal trials that led to the FDA approval of rasagiline, we challenged a subset of patients with very high doses of concentrated tyramine while they were on rasagiline. Of course this was performed in the Emergency Room or Intensive Care Units with all the blood pressure and cardiac monitors hooked up, just in case of a complication. We did not observe any rise in blood pressure or any adverse cardiac changes. In fact, most other drug regulating bodies in the other parts of the world do not impose this dietary restriction. The Germans, Italians, and Canadians, who probably consume more draft beer, red wine, pepperoni, sausages, and aged cheese in one meal (by the nature of their diet and not by the quantity of food they eat) than Americans would the entire day, do not carry this dietary restriction! So our message is, as long as you eat in moderation, don’t worry too much, bon appetit!

Also, my doctor told me that I cannot take rasagiline because I am on an anti-depressant. Is this true?

The combination of rasagiline (or selegiline) and some anti-depressants (such as the serotonin reuptake inhibitors or SSRIs and tricyclic antidepressants or TCAs) can lead to an uncomfortable and potentially dangerous phenomenon called serotonin syndrome. This syndrome is characterized by confusion, agitation, myoclonus (which are random twitches in different muscle groups), blood pressure and heart rate changes, to name a few. Therefore, whenever rasagiline or selegiline is prescribed, there is a warning not to combine these with certain anti-depressants.

The good news to report is that the chances of developing serotonin syndrome in patients treated with selegiline and an SSRI was found to be exceedingly rare: only 0.24%, with 0.04% experiencing a serious reaction (Richard et al 1997). Even better, in the large scale PRESTO trial with rasagiline, there was no difference in the adverse event rates between rasagiline-treated patients also receiving SSRIs and those not receiving SSRIs. Likewise, in a more recent safety analysis of 316 PD patients who took an antidepressant along with rasagiline, there were no unexpected adverse events or any evidence of serotonin toxicity (Panniset et al 2997). These patients were on amitriptyline, sertraline, paroxetine, trazodone, and citalopram. Thus, we have some confidence in combining rasagiline with these, but not necessarily all, anti-depressants.